The major goal of these studies is to investigate the mechanisms which operate to control the biosynthesis of heme in both the normal and abnormal states. Specifically this relates to a study of heme synthesis as related to erythroid development and the porphyrias. Delta-aminolevulinic acid synthetase (ALA-S), the initial enzyme in the heme biosynthetic chain, has been shown to be rate-limiting for the entire pathway. The synthesis of this enzyme appears to be under the control of a repressor-operator mechanism which is influenced by certain drugs and hormones, such as erythropoietin and sex steroid metabolites. Present studies are directed at determining the relationship of such chemical influence on porphyrin-heme synthesis to the porphyric diseases of man and to the physiologic control of erythropoiesis. Certain 5beta-H steroids, which have been shown to be capable of inducing ALA-S, will also be evaluated for their ability to stimulate hemoglobin synthesis in anemic man and for their possible role in the normal regulation of erythropoiesis and in the porphyrias.